Asthma, chronic obstructive pulmonary disease (COPD) and a restrictive spirometry pattern (RSP) are strongly associated with increased morbidity and mortality burden. Recent discoveries strongly suggest that the roots of many cases of asthma, COPD and RSP in adulthood can be found during early life. Prevention of these heterogeneous conditions, for which no cure currently exists, requires a thorough understanding of the natural history and mechanistic pathways that underlie their distinct clinical phenotypes. The Tucson Children's Respiratory Study (TCRS) has already made major contributions to our understanding of the natural history of asthma and of lung function trajectories and, as its participants are entering their fifth decade, is now poised to investigate, prospectively, the early risk factors for asthma, COPD and RSP as well as the molecular basis of their distinct clinical phenotypes. While the origins of atopic asthma (T2) are well established, the origins of non-T2 asthma, which is overrepresented among severe asthmatics and for which no efficacious treatment is available, are less well known. We recently showed that both high serum insulin and non-atopic rhinitis at the age of six years are strong, separate predictors of asthma from childhood up to age 36 years. These findings offer exciting new avenues to understand the pathogenesis of non-T2 asthma based on its natural history. Here, we propose to use state-of-the-art single-cell epigenetic and gene expression technologies to compare the cell type distribution in sputum of participants with and without these two early life risk factors. Regarding COPD, our recent findings suggest that at least half of all patients diagnosed with the disease do not show accelerated lung function decline during adult life, suggesting that airflow limitation had its origins in low airway function trajectories starting in childhood. We now propose to use CT imaging to determine the anatomical features of the persistently low airway function trajectory. In addition, we showed that smokers who had confirmed lower respiratory tract illnesses due to respiratory syncytial virus (RSV) in early life are at increased risk of having chronic respiratory symptoms in the third decade of life. We now propose to use data into the fifth decade of life to ascertain if the RSV-smoking interaction explains why only a minority of smokers develop COPD. Finally, we will investigate the hypothesis that major risk factors for RSP are nutritional problems in- utero and during childhood. We will address 3 specific aims: 1. To assess the cellular and molecular endotypes and the continued influence of early life risk factors on phenotypes of asthma from childhood into mid-adult life. 2. To assess the continued influence of early life risk factors and the clinical, physiological, and airway structural alterations of incipient early COPD in mid-adult life. 3. To assess the influence of early life risk factors on plethysmography-defined lung restriction in mid-adult life. As the only birth cohort with hundreds of non- selected participants followed from birth into the fifth decade of life, the TCRS offers a unique opportunity to investigate the potential disease mechanisms for the early origins of asthma, COPD, and RSP in adult life.